Alpha.sub.1 -Proteinase Inhibitor (.alpha..sub.1 -PI), also known as .alpha..sub.1 -antitrypsin, is a serum glycoprotein with a molecular weight of 52,000. Alpha.sub.1 -PI is synthesized in the liver and is present in the serum at levels between 150 and 350 mg/dl (equivalent to 30-80 .mu.M) when assayed with plasma standards.
Alpha.sub.1 -PI functions in the lungs to inhibit neutrophil elastase, a serine protease, which in large quantities can lead to the destruction of the alveolar walls. In the normal lung, .alpha..sub.1 -PI provides more than 90% of the anti-neutrophil elastase protection in the lower respiratory tract.
Alpha.sub.1 -PI deficiency is an autosomal, recessive hereditary disorder displayed by a large number of allelic variants and has been characterized into an allelic arrangement designated as the protease inhibitor (Pi) system. These alleles have been grouped on the basis of the .alpha..sub.1 -PI levels that occur in the serum of different individuals. Normal individuals have normal serum levels of .alpha..sub.1 -PI (normal individuals have been designated as having a PiMM phenotype). Deficient individuals have serum .alpha..sub.1 -PI levels of less than 35% of the average normal level (these individuals have been designated as having a PiZZ phenotype). Null individuals have undetectable .alpha..sub.1 -PI protein in their serum (these individuals have been designated as having a Pi(null)(null) phenotype).
Alpha.sub.1 -PI deficiency is characterized by low serum (less than 35% of average normal levels) and lung levels of .alpha..sub.1 -PI. These deficient individuals have a high risk of developing panacinar emphysema. This emphysema predominates in individuals who exhibit PiZZ, PiZ(null) and Pi(null) (null) phenotypes. Symptoms of the condition usually manifests in afflicted individuals in the third to fourth decades of life.
The emphysema associated with .alpha..sub.1 -PI deficiency develops as a result of insufficient .alpha..sub.1 -PI concentrations in the lower respiratory tract to inhibit neutrophil elastase, leading to destruction of the connective tissue framework of the lung parenchyma. Individuals with .alpha..sub.1 -PI deficiency have little protection against the neutrophil elastase released by the neutrophils in their lower respiratory tract. This imbalance of protease:protease inhibitor in .alpha..sub.1 -PI deficient individuals results in chronic damage to, and ultimately destruction of the lung parenchyma and alveolar walls.
Individuals with severe .alpha..sub.1 -PI deficiency typically exhibit endogenous serum .alpha..sub.1 -PI levels of less than 50 mg/dl, as determined by commercial standards. Individuals with these low serum .alpha..sub.1 -PI levels have greater than an 80% risk of developing emphysema over a lifetime. It is estimated that at least 40,000 patients in the United States, or 2% of all those with emphysema, have this disease resulting from a defect in the gene coding for .alpha..sub.1 -PI. A deficiency in .alpha..sub.1 -PI represents one of the most common lethal hereditary disorders of Caucasians in the United States and Europe.
Therapy for patients with .alpha..sub.1 -PI deficiency is directed towards replacement or augmentation of .alpha..sub.1 -PI levels in the serum. If serum levels of .alpha..sub.1 -PI are increased, this is expected to lead to higher concentrations in the lungs and thus correct the neutrophil elastase:.alpha..sub.1 -PI imbalance in the lungs and prevent or slow destruction of lung tissue. Studies of normal and .alpha..sub.1 -PI deficient populations have suggested that the minimum protective serum .alpha..sub.1 -PI levels are 80 mg/dl or 11 .mu.M (about 57 mg/dl; using pure standards). Consequently, most augmentation therapy in .alpha..sub.1 -PI deficient patients is aimed toward providing the minimum protective serum level of .alpha..sub.1 -PI, since serum .alpha..sub.1 -PI is the source of alveolar .alpha..sub.1 -PI.
Alpha.sub.1 -PI preparations have been available for therapeutic use since the mid 1980's. The major use has been augmentation (replacement) therapy for congenital .alpha..sub.1 -PI deficiency. The half-live of human .alpha..sub.1 -PI in vivo is 4.38 days with a standard deviation of 1.27 days. The currently recommended dosage of 60 mg .alpha..sub.1 -PI/kg body weight weekly will restore low serum levels of .alpha..sub.1 -PI to levels above the protective threshold level of 11 .mu.M or 80 mg/dl.
Previously .alpha..sub.1 -PI has been purified by various techniques. One such process combined chromatography on an anion-exchange chromatography medium followed by PEG precipitation. Other purification procedures have used PEG precipitation followed by anion-exchange chromatography and others have used multiple PEG precipitation steps followed by anion-exchange chromatography. Still other methods have used phase separation techniques to purify .alpha..sub.1 -PI. Specific activities of 1.26 units/mg have been reported for purified .alpha..sub.1 -PI.